Nanotechnology has received extraordinary attention recently due to its burgeoning role in biomedical science. The materials composing the nanoparticles produce fascinating and diverse functionalities as a result of their exceptionally small size. In fact, even seemingly insignificant changes in particle size can have profound effects on these properties. Thus size control, both during synthesis and in particle suspensions, is a sine qua non for functionality. This can be accomplished by masking the particle surface with a multitude of different ligands. Not only can surface ligands constrain the growth of nucleation, they can also direct the shape of crystallization. However no single ligand can do everything. Fortunately ligands are essentially fungible and can be exchanged at various times to confer the desired properties to the particle. This can include protecting the particle from harsh aqueous conditions, such as pH extremes, maximizing optical properties for diagnostics or shielding the particle from potentially hostile conditions found in the body. Because these moieties interact ubiquitously with various biological materials, particularly proteins, there needs to be a rationalized design of surface ligands. The design of the ligand can have crucial effects on biodistribution as well as evasion of biological defenses. Ligands can even be designed to provide new functionality in response to various environmental stimuli to improve their therapeutic or diagnostic capabilities. Considering the importance of ligands then on this emerging field, this review will thoroughly consider the ligand design for the various steps of nanodevelopment, from synthesis and assembly through biomedical translation. (C) 2014 Elsevier Ltd. All rights reserved.